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1. A modified γ-retrovirus vector for X-linked severe combined immunodeficiency

Author

Hacein-Bey-Abina, S, Pai, SY, Gaspar, HB, Armant, M, Berry, CC, Blanche, S, Bleesing, J, Blondeau, J, De Boer, H, Buckland, KF, Caccavelli, L, Cros, G, De Oliveira, S, Fernández, KS, Guo, D, Harris, CE, Hopkins, G, Lehmann, LE, Lim, A, London, WB, Van Der Loo, JCM, Malani, N, Male, F, Malik, P, Marinovic, MA, McNicol, AM, Moshous, D, Neven, B, Oleastro, M, Picard, C, Ritz, J, Rivat, C, Schambach, A, Shaw, KL, Sherman, EA, Silberstein, LE, Six, E, Touzot, F, Tsytsykova, A, Xu-Bayford, J, Baum, C, Bushman, FD, Fischer, A, Kohn, DB, Filipovich, AH, Notarangelo, LD, Cavazzana, M, Williams, DA, and Thrasher, AJ

Abstract

Copyright © 2014 Massachusetts Medical Society. All rights reserved. BACKGROUND In previous clinical trials involving children with X-linked severe combined immunodeficiency (SCID-X1), a Moloney murine leukemia virus-based γ-retrovirus vector expressing interleukin-2 receptor γ-chain (γc) complementary DNA successfully restored immunity in most patients but resulted in vector-induced leukemia through enhancermediated mutagenesis in 25% of patients. We assessed the efficacy and safety of a self-inactivating retrovirus for the treatment of SCID-X1.METHODS We enrolled nine boys with SCID-X1 in parallel trials in Europe and the United States to evaluate treatment with a self-inactivating (SIN) γ-retrovirus vector containing deletions in viral enhancer sequences expressing γc (SIN-γc).RESULTS All patients received bone marrow-derived CD34+ cells transduced with the SIN-γc vector, without preparative conditioning. After 12.1 to 38.7 months of follow-up, eight of the nine children were still alive. One patient died from an overwhelming adenoviral infection before reconstitution with genetically modified T cells. Of the remaining eight patients, seven had recovery of peripheral-blood T cells that were functional and led to resolution of infections. The patients remained healthy thereafter. The kinetics of CD3+ T-cell recovery was not significantly different from that observed in previous trials. Assessment of insertion sites in peripheral blood from patients in the current trial as compared with those in previous trials revealed significantly less clustering of insertion sites within LMO2, MECOM, and other lymphoid proto-oncogenes in our patients.CONCLUSIONS This modified γ-retrovirus vector was found to retain efficacy in the treatment of SCID-X1. The long-term effect of this therapy on leukemogenesis remains unknown.

Published
2014

2. Comparison of outcomes of hematopoietic stem cell transplantation without chemotherapy conditioning by using matched sibling and unrelated donors for treatment of severe combined immunodeficiency

Author

Dvorak, CC, Hassan, A, Slatter, MA, Hönig, M, Lankester, AC, Buckley, RH, Pulsipher, MA, Davis, JH, Güngör, T, Gabriel, M, Bleesing, JH, Bunin, N, Sedlacek, P, Connelly, JA, Crawford, DF, Notarangelo, LD, Pai, SY, Hassid, J, Veys, P, Gennery, AR, and Cowan, MJ

Subjects
Immunology, Allergy
Abstract

Background Patients with severe combined immunodeficiency disease who have matched sibling donors (MSDs) can proceed to hematopoietic cell transplantation (HCT) without conditioning chemotherapy. Objective We sought to determine whether the results of HCT without chemotherapy-based conditioning from matched unrelated donors (URDs), either from volunteer adults or umbilical cord blood, are comparable with those from MSDs.

Published
2014

3. Hematopoietic Stem Cell Transplantation in Late-onset X-linked Chronic Granulomatous Disease in a Female Carrier

Author

Trevisan M, Kang EM, Salton F, Ruaro B, Torregiani C, Confalonieri P, Naviglio S, Valencic E, Gabrielli M, Parta M, Kelly C, Notarangelo LD, Malech HL, Tommasini A, Confalonieri M., Trevisan, M, Kang, Em, Salton, F, Ruaro, B, Torregiani, C, Confalonieri, P, Naviglio, S, Valencic, E, Gabrielli, M, Parta, M, Kelly, C, Notarangelo, Ld, Malech, Hl, Tommasini, A, and Confalonieri, M.

Subjects
Interferon-gamma, Transplantation Conditioning, Immunology, Hematopoietic Stem Cell Transplantation, Humans, Immunology and Allergy, Female, Chronic Granulomatous Disease, Granulomatous Disease, Chronic, Article
Abstract

Chronic granulomatous disease (CGD) is a rare immunodeficiency disorder characterized by a defective NADPH oxidase complex leading to an impaired respiratory burst and defective killing of pathogens by phagocytes. The most common type of CGD is caused by hemizygous mutations of the CYBB gene on the X chromosome encoding the gp91phox subunit. It usually affects males, yet heterozygous females may rarely manifest clinical signs of the disease due to skewed X chromosome inactivation in leukocytes . Despite advances in gene therapy, hematopoietic stem cell transplantation (HSCT) remains the main definitive treatment. Older patients, however, are at greater risk of HSCT-related complications and mortality and may require a specific approach.

Published
2022
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4. Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Author

Medicina i Cirurgia, Universitat Rovira i Virgili, Matuozzo, D; Talouarn, E; Marchal, A; Zhang, P; Manry, J; Seeleuthner, Y; Zhang, Y; Bolze, A; Chaldebas, M; Milisavljevic, B; Gervais, A; Bastard, P; Asano, T; Bizien, L; Barzaghi, F; Abolhassani, H; Abou Tayoun, A; Aiuti, A; Alavi Darazam, I; Allende, LM; Alonso-Arias, R; Arias, AA; Aytekin, G; Bergman, P; Bondesan, S; Bryceson, YT; Bustos, IG; Cabrera-Marante, O; Carcel, S; Carrera, P; Casari, G; Chaïbi, K; Colobran, R; Condino-Neto, A; Covill, LE; Delmonte, OM; El Zein, L; Flores, C; Gregersen, PK; Gut, M; Haerynck, F; Halwani, R; Hancerli, S; Hammarström, L; Hatipoglu, N; Karbuz, A; Keles, S; Kyheng, C; Leon-Lopez, R; Franco, JL; Mansouri, D; Martinez-Picado, J; Metin Akcan, O; Migeotte, I; Morange, PE; Morelle, G; Martin-Nalda, A; Novelli, G; Novelli, A; Ozcelik, T; Palabiyik, F; Pan-Hammarström, Q; de Diego, RP; Planas-Serra, L; Pleguezuelo, DE; Prando, C; Pujol, A; Reyes, LF; Rivière, JG; Rodriguez-Gallego, C; Rojas, J; Rovere-Querini, P; Schlüter, A; Shahrooei, M; Sobh, A; Soler-Palacin, P; Tandjaoui-Lambiotte, Y; Tipu, I; Tresoldi, C; Troya, J; van de Beek, D; Zatz, M; Zawadzki, P; Al-Muhsen, SZ; Alosaimi, MF; Alsohime, FM; Baris-Feldman, H; Butte, MJ; Constantinescu, SN; Cooper, MA; Dalgard, CL; Fellay, J; Heath, JR; Lau, YL; Lifton, RP; Maniatis, T; Mogensen, TH; von Bernuth, H; Lermine, A; Vidaud, M; Boland, A; Deleuze, JF; Nussbaum, R; Kahn-Kirby, A; Mentre, F; Tubiana, S; Gorochov, G; Tubach, F; Hausfater, P; Effort, CHG; Meyts, I; Zhang, SY; Puel, A; Notarangelo, LD; Boisson-Dupuis, S; Su, HC; Boisson, B; Jouanguy, E; Casanova, JL; Zhang, Q; Abel, L; Cobat, A, Medicina i Cirurgia, Universitat Rovira i Virgili, and Matuozzo, D; Talouarn, E; Marchal, A; Zhang, P; Manry, J; Seeleuthner, Y; Zhang, Y; Bolze, A; Chaldebas, M; Milisavljevic, B; Gervais, A; Bastard, P; Asano, T; Bizien, L; Barzaghi, F; Abolhassani, H; Abou Tayoun, A; Aiuti, A; Alavi Darazam, I; Allende, LM; Alonso-Arias, R; Arias, AA; Aytekin, G; Bergman, P; Bondesan, S; Bryceson, YT; Bustos, IG; Cabrera-Marante, O; Carcel, S; Carrera, P; Casari, G; Chaïbi, K; Colobran, R; Condino-Neto, A; Covill, LE; Delmonte, OM; El Zein, L; Flores, C; Gregersen, PK; Gut, M; Haerynck, F; Halwani, R; Hancerli, S; Hammarström, L; Hatipoglu, N; Karbuz, A; Keles, S; Kyheng, C; Leon-Lopez, R; Franco, JL; Mansouri, D; Martinez-Picado, J; Metin Akcan, O; Migeotte, I; Morange, PE; Morelle, G; Martin-Nalda, A; Novelli, G; Novelli, A; Ozcelik, T; Palabiyik, F; Pan-Hammarström, Q; de Diego, RP; Planas-Serra, L; Pleguezuelo, DE; Prando, C; Pujol, A; Reyes, LF; Rivière, JG; Rodriguez-Gallego, C; Rojas, J; Rovere-Querini, P; Schlüter, A; Shahrooei, M; Sobh, A; Soler-Palacin, P; Tandjaoui-Lambiotte, Y; Tipu, I; Tresoldi, C; Troya, J; van de Beek, D; Zatz, M; Zawadzki, P; Al-Muhsen, SZ; Alosaimi, MF; Alsohime, FM; Baris-Feldman, H; Butte, MJ; Constantinescu, SN; Cooper, MA; Dalgard, CL; Fellay, J; Heath, JR; Lau, YL; Lifton, RP; Maniatis, T; Mogensen, TH; von Bernuth, H; Lermine, A; Vidaud, M; Boland, A; Deleuze, JF; Nussbaum, R; Kahn-Kirby, A; Mentre, F; Tubiana, S; Gorochov, G; Tubach, F; Hausfater, P; Effort, CHG; Meyts, I; Zhang, SY; Puel, A; Notarangelo, LD; Boisson-Dupuis, S; Su, HC; Boisson, B; Jouanguy, E; Casanova, JL; Zhang, Q; Abel, L; Cobat, A

Abstract

Abstract Background We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in?~?80% of cases. Methods We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P?=?1.1?×?10?4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR?=?3.70[95%CI 1.3–8.2], P?=?2.1?×?10?4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR?

Published
2023

5. Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Author

Matuozzo, D, Talouarn, E, Marchal, A, Zhang, P, Manry, J, Seeleuthner, Y, Zhang, Y, Bolze, A, Chaldebas, M, Milisavljevic, B, Gervais, A, Bastard, P, Asano, T, Bizien, L, Barzaghi, F, Abolhassani, H, Abou Tayoun, A, Aiuti, A, Alavi Darazam, I, Allende, Lm, Alonso-Arias, R, Arias, Aa, Aytekin, G, Bergman, P, Bondesan, S, Bryceson, Yt, Bustos, Ig, Cabrera-Marante, O, Carcel, S, Carrera, P, Casari, G, Chaïbi, K, Colobran, R, Condino-Neto, A, Covill, Le, Delmonte, Om, El Zein, L, Flores, C, Gregersen, Pk, Gut, M, Haerynck, F, Halwani, R, Hancerli, S, Hammarström, L, Hatipoğlu, N, Karbuz, A, Keles, S, Kyheng, C, Leon-Lopez, R, Franco, Jl, Mansouri, D, Martinez-Picado, J, Metin Akcan, O, Migeotte, I, Morange, P, Morelle, G, Martin-Nalda, A, Novelli, G, Novelli, A, Ozcelik, T, Palabiyik, F, Pan-Hammarström, Q, de Diego, Rp, Planas-Serra, L, Pleguezuelo, De, Prando, C, Pujol, A, Reyes, Lf, Rivière, Jg, Rodriguez-Gallego, C, Rojas, J, Rovere-Querini, P, Schlüter, A, Shahrooei, M, Sobh, A, Soler-Palacin, P, Tandjaoui-Lambiotte, Y, Tipu, I, Tresoldi, C, Troya, J, van de Beek, D, Zatz, M, Zawadzki, P, Al-Muhsen, Sz, Alosaimi, Mf, Alsohime, Fm, Baris-Feldman, H, Butte, Mj, Constantinescu, Sn, Cooper, Ma, Dalgard, Cl, Fellay, J, Heath, Jr, Lau, Y, Lifton, Rp, Maniatis, T, Mogensen, Th, von Bernuth, H, Lermine, A, Vidaud, M, Boland, A, Deleuze, J, Nussbaum, R, Kahn-Kirby, A, Mentre, F, Tubiana, S, Gorochov, G, Tubach, F, Hausfater, P, Meyts, I, Zhang, S, Puel, A, Notarangelo, Ld, Boisson-Dupuis, S, Helen C, S, Boisson, B, Jouanguy, E, Casanova, J, Zhang, Q, Abel, L, and Cobat, A

Subjects
Settore MED/03, Immunity, COVID-19, Rare variants, Type I interferon
Published
2023

6. Harnessing Type I IFN immunity against SARS-CoV-2 with early administration of IFN-β

Author

Vinh, Dc, Abel, L, Bastard, P, Cheng, Mp, Condino-Neto, A, Gregersen, Pk, Haerynck, F, Cicalese, M, Hagin, D, Soler-Palacin, P, Planas, Am, Pujol, A, Notarangelo, Ld, Zhang, Q, H. C., S, Casanova, J, Meyts, I, Aiuti, A, Arkin, Lm, Bolze, A, Charkravorty, S, Christodoulou, J, Colobran, R, Drolet, Ba, Fellay, J, Froidure, Pa, Pape, Jw, Halwani, R, Mogensen, Th, Novelli, G, Resnick, Ib, Sediva, A, Tancevski, I, Turvey, S, Vinh, Donald C, Abel, Laurent, Bastard, Paul, Cheng, Matthew P, Condino-Neto, Antonio, Gregersen, Peter K, Haerynck, Filomeen, Cicalese, Maria-Pia, Hagin, David, Soler-Palacín, Pere, Planas, Anna M, Pujol, Aurora, Notarangelo, Luigi D, Zhang, Qian, Su, Helen C, Casanova, Jean-Laurent, and Meyts, Isabelle

Subjects
0301 basic medicine, 2019-20 coronavirus outbreak, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Immunology, Library science, Lymphocyte Depletion, 03 medical and health sciences, 0302 clinical medicine, Political science, Triple combination, Immunology and Allergy, Animals, Humans, Integrative biology, Protein Kinase Inhibitors, COVID-19 Serotherapy, Autoantibodies, B-Lymphocytes, SARS-CoV-2, Vaccination, Immunization, Passive, COVID-19, Immunoglobulins, Intravenous, Interferon-beta, Plasmapheresis, ESTUDOS DE COORTES, 030104 developmental biology, Infectious Diseases / Laboratory, Settore MED/03, Interferon Type I, Clinical and Translational Science Award, Commentary, Immunotherapy, Translational science, Administration (government), 030215 immunology
Abstract

D.C.V. is supported by the Fonds de la recherche en sante du Quebec clinician-scientist scholar Junior 2 program. L.D.N. and H.C.S. are supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH) (R01AI088364), the National Center for Advancing Translational Sciences (NCATS), NIH Clinical and Translational Science Award (CTSA) program (UL1 TR001866), a Fast Grant from Emergent Ventures, Mercatus Center at George Mason University, the Yale Center for Mendelian Genomics and the GSP Coordinating Center funded by the National Human Genome Research Institute (NHGRI) (UM1HG006504 and U24HG008956), the Fisher Center for Alzheimer’s Research Foundation, the Meyer Foundation, the French National Research Agency (ANR) under the “Investments for the Future” program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (FRM) (EQU201903007798), the FRM and ANR GENCOVID project, ANRS-COV05, the Square Foundation, Grandir - Fonds de solidarite pour l’enfance, the SCOR Corporate Foundation for Science, Institut National de la Sante et de la Recherche Medicale (INSERM), and the University of Paris. PB is supported by the MD-PhD program of the Imagine Institute (with the support of the Fondation Bettencourt-Schueller). I.M. is a Senior Clinical Investigator at the Research Foundation – Flanders, and is chair of the CSL Behring Chair of Primary Immunodeficiencies at KU Leuven, by the KU Leuven C1 Grant C16/18/007, by a VIB GC PID Grant, by the FWO Grants G0C8517N, G0B5120N, and G0E8420N, and by the Jeffrey Modell Foundation. This work is supported by ERN-RITA.

Published
2021

11. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19

Author

Zhang, Q, Liu, Z, Moncada-Velez, M, Chen, J, Ogishi, M, Bigio, B, Yang, R, Arias, AA, Zhou, Q, Han, JE, Ugurbil, AC, Zhang, P, Rapaport, F, Li, J, Spaan, AN, Boisson, B, Boisson-Dupuis, S, Bustamante, J, Puel, A, Ciancanelli, MJ, Zhang, SY, Béziat, V, Jouanguy, E, Abel, L, Cobat, A, Casanova, JL, Bastard, P, Korol, C, Rosain, J, Philippot, Q, Chbihi, M, Lorenzo, L, Bizien, L, Neehus, AL, Kerner, G, Seeleuthner, Y, Manry, J, Le Voyer, T, Le Pen, J, Schneider, WM, Razooky, BS, Hoffmann, HH, Michailidis, E, Rice, CM, Sabli, IKD, Hodeib, S, Sancho-Shimizu, V, Bilguvar, K, Ye, J, Maniatis, T, Bolze, A, Zhang, Y, Notarangelo, LD, Su, HC, Onodi, F, Korniotis, S, Karpf, L, Soumelis, V, Bonnet-Madin, L, Amara, A, Dorgham, K, Gorochov, G, Smith, N, Duffy, D, Moens, L, Meyts, I, Zhang, Q, Liu, Z, Moncada-Velez, M, Chen, J, Ogishi, M, Bigio, B, Yang, R, Arias, AA, Zhou, Q, Han, JE, Ugurbil, AC, Zhang, P, Rapaport, F, Li, J, Spaan, AN, Boisson, B, Boisson-Dupuis, S, Bustamante, J, Puel, A, Ciancanelli, MJ, Zhang, SY, Béziat, V, Jouanguy, E, Abel, L, Cobat, A, Casanova, JL, Bastard, P, Korol, C, Rosain, J, Philippot, Q, Chbihi, M, Lorenzo, L, Bizien, L, Neehus, AL, Kerner, G, Seeleuthner, Y, Manry, J, Le Voyer, T, Le Pen, J, Schneider, WM, Razooky, BS, Hoffmann, HH, Michailidis, E, Rice, CM, Sabli, IKD, Hodeib, S, Sancho-Shimizu, V, Bilguvar, K, Ye, J, Maniatis, T, Bolze, A, Zhang, Y, Notarangelo, LD, Su, HC, Onodi, F, Korniotis, S, Karpf, L, Soumelis, V, Bonnet-Madin, L, Amara, A, Dorgham, K, Gorochov, G, Smith, N, Duffy, D, Moens, L, and Meyts, I

Abstract

Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)- and interferon regulatory factor 7 (IRF7)-dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.

Published
2020

12. Autoantibodies against type I IFNs in patients with life-threatening COVID-19

Author

Bastard, P, Rosen, LB, Zhang, Q, Michailidis, E, Hoffmann, HH, Zhang, Y, Dorgham, K, Philippot, Q, Rosain, J, Béziat, V, Manry, J, Shaw, E, Haljasmägi, L, Peterson, P, Lorenzo, L, Bizien, L, Trouillet-Assant, S, Dobbs, K, de Jesus, AA, Belot, A, Kallaste, A, Catherinot, E, Tandjaoui-Lambiotte, Y, Le Pen, J, Kerner, G, Bigio, B, Seeleuthner, Y, Yang, R, Bolze, A, Spaan, AN, Delmonte, OM, Abers, MS, Aiuti, A, Casari, G, Lampasona, V, Piemonti, L, Ciceri, F, Bilguvar, K, Lifton, RP, Vasse, M, Smadja, DM, Migaud, M, Hadjadj, J, Terrier, B, Duffy, D, Quintana-Murci, L, van de Beek, D, Roussel, L, Vinh, DC, Tangye, SG, Haerynck, F, Dalmau, D, Martinez-Picado, J, Brodin, P, Nussenzweig, MC, Boisson-Dupuis, S, Rodríguez-Gallego, C, Vogt, G, Mogensen, TH, Oler, AJ, Gu, J, Burbelo, PD, Cohen, JI, Biondi, A, Bettini, LR, DÁngio, M, Bonfanti, P, Rossignol, P, Mayaux, J, Rieux-Laucat, F, Husebye, ES, Fusco, F, Ursini, MV, Imberti, L, Sottini, A, Paghera, S, Quiros-Roldan, E, Rossi, C, Castagnoli, R, Montagna, D, Licari, A, Marseglia, GL, Duval, X, Ghosn, J, Tsang, JS, Goldbach-Mansky, R, Kisand, K, Lionakis, MS, Puel, A, Zhang, SY, Holland, SM, Gorochov, G, Jouanguy, E, Rice, CM, Cobat, A, Notarangelo, LD, Abel, L, Su, HC, Casanova, JL, Arias, AA, Bastard, P, Rosen, LB, Zhang, Q, Michailidis, E, Hoffmann, HH, Zhang, Y, Dorgham, K, Philippot, Q, Rosain, J, Béziat, V, Manry, J, Shaw, E, Haljasmägi, L, Peterson, P, Lorenzo, L, Bizien, L, Trouillet-Assant, S, Dobbs, K, de Jesus, AA, Belot, A, Kallaste, A, Catherinot, E, Tandjaoui-Lambiotte, Y, Le Pen, J, Kerner, G, Bigio, B, Seeleuthner, Y, Yang, R, Bolze, A, Spaan, AN, Delmonte, OM, Abers, MS, Aiuti, A, Casari, G, Lampasona, V, Piemonti, L, Ciceri, F, Bilguvar, K, Lifton, RP, Vasse, M, Smadja, DM, Migaud, M, Hadjadj, J, Terrier, B, Duffy, D, Quintana-Murci, L, van de Beek, D, Roussel, L, Vinh, DC, Tangye, SG, Haerynck, F, Dalmau, D, Martinez-Picado, J, Brodin, P, Nussenzweig, MC, Boisson-Dupuis, S, Rodríguez-Gallego, C, Vogt, G, Mogensen, TH, Oler, AJ, Gu, J, Burbelo, PD, Cohen, JI, Biondi, A, Bettini, LR, DÁngio, M, Bonfanti, P, Rossignol, P, Mayaux, J, Rieux-Laucat, F, Husebye, ES, Fusco, F, Ursini, MV, Imberti, L, Sottini, A, Paghera, S, Quiros-Roldan, E, Rossi, C, Castagnoli, R, Montagna, D, Licari, A, Marseglia, GL, Duval, X, Ghosn, J, Tsang, JS, Goldbach-Mansky, R, Kisand, K, Lionakis, MS, Puel, A, Zhang, SY, Holland, SM, Gorochov, G, Jouanguy, E, Rice, CM, Cobat, A, Notarangelo, LD, Abel, L, Su, HC, Casanova, JL, and Arias, AA

Abstract

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-w (IFN-w) (13 patients), against the 13 types of IFN-a (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men.

Published
2020

13. The Clinical and Genetic Spectrum of 82 Patients WithRAGDeficiency Including a c.256_257delAA Founder Variant in Slavic Countries

Author

Sharapova, SO, Skomska-Pawliszak, M, Rodina, YA, Wolska-Kusnierz, B, Dabrowska-Leonik, N, Mikoluc, B, Pashchenko, OE, Pasic, S, Freiberger, T, Milota, T, Formankova, R, Szaflarska, A, Siedlar, M, Avcin, T, Markelj, G, Ciznar, P, Kalwak, K, Kottan, S, Jackowska, T, Drabko, K, Gagro, A, Pac, M, Naumova, E, Kandilarova, S, Babol-Pokora, K, Varabyou, DS, Barendregt, Barbara, Raykina, EV, Varlamova, TV, Pavlova, AV, Grombirikova, H, Debeljak, M, Mersiyanova, IV, Bondarenko, AV, Chernyshova, LI, Kostyuchenko, LV, Guseva, MN, Rascon, J, Muleviciene, A, Preiksaitiene, E, Geier, CB, Leiss-Piller, A, Yamazaki, Y, Kawai, T, Walter, JE, Kondratenko, IV, Sediva, A, van der Burg, Mirjam, Kuzmenko, NB, Notarangelo, LD, Bernatowska, E, Aleinikova, OV, Sharapova, SO, Skomska-Pawliszak, M, Rodina, YA, Wolska-Kusnierz, B, Dabrowska-Leonik, N, Mikoluc, B, Pashchenko, OE, Pasic, S, Freiberger, T, Milota, T, Formankova, R, Szaflarska, A, Siedlar, M, Avcin, T, Markelj, G, Ciznar, P, Kalwak, K, Kottan, S, Jackowska, T, Drabko, K, Gagro, A, Pac, M, Naumova, E, Kandilarova, S, Babol-Pokora, K, Varabyou, DS, Barendregt, Barbara, Raykina, EV, Varlamova, TV, Pavlova, AV, Grombirikova, H, Debeljak, M, Mersiyanova, IV, Bondarenko, AV, Chernyshova, LI, Kostyuchenko, LV, Guseva, MN, Rascon, J, Muleviciene, A, Preiksaitiene, E, Geier, CB, Leiss-Piller, A, Yamazaki, Y, Kawai, T, Walter, JE, Kondratenko, IV, Sediva, A, van der Burg, Mirjam, Kuzmenko, NB, Notarangelo, LD, Bernatowska, E, and Aleinikova, OV

Published
2020

14. Auto-antibodies against type I IFNs in patients with life-threatening COVID-19

Author

Universitat Rovira i Virgili, Bastard P; Rosen LB; Zhang Q; Michailidis E; Hoffmann HH; Zhang Y; Dorgham K; Philippot Q; Rosain J; Béziat V; Manry J; Shaw E; Haljasmägi L; Peterson P; Lorenzo L; Bizien L; Trouillet-Assant S; Dobbs K; de Jesus AA; Belot A; Kallaste A; Catherinot E; Tandjaoui-Lambiotte Y; Le Pen J; Kerner G; Bigio B; Seeleuthner Y; Yang R; Bolze A; Spaan AN; Delmonte OM; Abers MS; Aiuti A; Casari G; Lampasona V; Piemonti L; Ciceri F; Bilguvar K; Lifton RP; Vasse M; Smadja DM; Migaud M; Hadjadj J; Terrier B; Duffy D; Quintana-Murci L; van de Beek D; Roussel L; Vinh DC; Tangye SG; Haerynck F; Dalmau D; Martinez-Picado J; Brodin P; Nussenzweig MC; Boisson-Dupuis S; Rodríguez-Gallego C; Vogt G; Mogensen TH; Oler AJ; Gu J; Burbelo PD; Cohen J; Biondi A; Bettini LR; D'Angio M; Bonfanti P; Rossignol P; Mayaux J; Rieux-Laucat F; Husebye ES; Fusco F; Ursini MV; Imberti L; Sottini A; Paghera S; Quiros-Roldan E; Rossi C; Castagnoli R; Montagna D; Licari A; Marseglia GL; Duval X; Ghosn J; HGID Lab; NIAID-USUHS Immune Response to COVID Group; COVID Clinicians; COVID-STORM Clinicians; Imagine COVID Group; French COVID Cohort Study Group; Milieu Intérieur Consortium; CoV-Contact Cohort; Amsterdam UMC Covid-19 Biobank; COVID Human Genetic Effort; Tsang JS; Goldbach-Mansky R; Kisand K; Lionakis MS; Puel A; Zhang SY; Holland SM; Gorochov G; Jouanguy E; Rice CM; Cobat A; Notarangelo LD; Abel L; Su HC; Casanova JL, Universitat Rovira i Virgili, and Bastard P; Rosen LB; Zhang Q; Michailidis E; Hoffmann HH; Zhang Y; Dorgham K; Philippot Q; Rosain J; Béziat V; Manry J; Shaw E; Haljasmägi L; Peterson P; Lorenzo L; Bizien L; Trouillet-Assant S; Dobbs K; de Jesus AA; Belot A; Kallaste A; Catherinot E; Tandjaoui-Lambiotte Y; Le Pen J; Kerner G; Bigio B; Seeleuthner Y; Yang R; Bolze A; Spaan AN; Delmonte OM; Abers MS; Aiuti A; Casari G; Lampasona V; Piemonti L; Ciceri F; Bilguvar K; Lifton RP; Vasse M; Smadja DM; Migaud M; Hadjadj J; Terrier B; Duffy D; Quintana-Murci L; van de Beek D; Roussel L; Vinh DC; Tangye SG; Haerynck F; Dalmau D; Martinez-Picado J; Brodin P; Nussenzweig MC; Boisson-Dupuis S; Rodríguez-Gallego C; Vogt G; Mogensen TH; Oler AJ; Gu J; Burbelo PD; Cohen J; Biondi A; Bettini LR; D'Angio M; Bonfanti P; Rossignol P; Mayaux J; Rieux-Laucat F; Husebye ES; Fusco F; Ursini MV; Imberti L; Sottini A; Paghera S; Quiros-Roldan E; Rossi C; Castagnoli R; Montagna D; Licari A; Marseglia GL; Duval X; Ghosn J; HGID Lab; NIAID-USUHS Immune Response to COVID Group; COVID Clinicians; COVID-STORM Clinicians; Imagine COVID Group; French COVID Cohort Study Group; Milieu Intérieur Consortium; CoV-Contact Cohort; Amsterdam UMC Covid-19 Biobank; COVID Human Genetic Effort; Tsang JS; Goldbach-Mansky R; Kisand K; Lionakis MS; Puel A; Zhang SY; Holland SM; Gorochov G; Jouanguy E; Rice CM; Cobat A; Notarangelo LD; Abel L; Su HC; Casanova JL

Abstract

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-omega (IFN-omega) (13 patients), against the 13 types of IFN-alpha (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for lifethreatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men.

Published
2020

15. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19

Author

Universitat Rovira i Virgili, Zhang Q, Bastard P, Liu Z, Le Pen J, Moncada-Velez M, Chen J, Ogishi M, Sabli IKD, Hodeib S, Korol C, Rosain J, Bilguvar K, Ye J, Bolze A, Bigio B, Yang R, Arias AA, Zhou Q, Zhang Y, Onodi F, Korniotis S, Karpf L, Philippot Q, Chbihi M, Bonnet-Madin L, Dorgham K, Smith N, Schneider WM, Razooky BS, Hoffmann HH, Michailidis E, Moens L, Han JE, Lorenzo L, Bizien L, Meade P, Neehus AL, Ugurbil AC, Corneau A, Kerner G, Zhang P, Rapaport F, Seeleuthner Y, Manry J, Masson C, Schmitt Y, Schlüter A, Le Voyer T, Khan T, Li J, Fellay J, Roussel L, Shahrooei M, Alosaimi MF, Mansouri D, Al-Saud H, Al-Mulla F, Almourfi F, Al-Muhsen SZ, Alsohime F, Al Turki S, Hasanato R, van de Beek D, Biondi A, Bettini LR, D'Angio M, Bonfanti P, Imberti L, Sottini A, Paghera S, Quiros-Roldan E, Rossi C, Oler AJ, Tompkins MF, Alba C, Vandernoot I, Goffard JC, Smits G, Migeotte I, Haerynck F, Soler-Palacin P, Martin-Nalda A, Colobran R, Morange PE, Keles S, Çölkesen F, Ozcelik T, Yasar KK, Senoglu S, Karabela ?N, Gallego CR, Novelli G, Hraiech S, Tandjaoui-Lambiotte Y, Duval X, Laouénan C,, Snow AL, Dalgard CL, Milner J, Vinh DC, Mogensen TH, Marr N, Spaan AN, Boisson B, Boisson-Dupuis S, Bustamante J, Puel A, Ciancanelli M, Meyts I, Maniatis T, Soumelis V, Amara A, Nussenzweig M, García-Sastre A, Krammer F, Pujol A, Duffy D, Lifton R, Zhang SY, Gorochov G, Béziat V, Jouanguy E, Sancho-Shimizu V, Rice CM, Abel L, Notarangelo LD, Cobat A, Su HC, Casanova JL COVID-STORM Clinicians, COVID Clinicians, Imagine COVID Group, French COVID Cohort Study Group, CoV-Contact Cohort, Amsterdam UMC Covid-19, Biobank, COVID Human Genetic Effort, NIAID-USUHS, TAGC COVID Immunity Group, Universitat Rovira i Virgili, and Zhang Q, Bastard P, Liu Z, Le Pen J, Moncada-Velez M, Chen J, Ogishi M, Sabli IKD, Hodeib S, Korol C, Rosain J, Bilguvar K, Ye J, Bolze A, Bigio B, Yang R, Arias AA, Zhou Q, Zhang Y, Onodi F, Korniotis S, Karpf L, Philippot Q, Chbihi M, Bonnet-Madin L, Dorgham K, Smith N, Schneider WM, Razooky BS, Hoffmann HH, Michailidis E, Moens L, Han JE, Lorenzo L, Bizien L, Meade P, Neehus AL, Ugurbil AC, Corneau A, Kerner G, Zhang P, Rapaport F, Seeleuthner Y, Manry J, Masson C, Schmitt Y, Schlüter A, Le Voyer T, Khan T, Li J, Fellay J, Roussel L, Shahrooei M, Alosaimi MF, Mansouri D, Al-Saud H, Al-Mulla F, Almourfi F, Al-Muhsen SZ, Alsohime F, Al Turki S, Hasanato R, van de Beek D, Biondi A, Bettini LR, D'Angio M, Bonfanti P, Imberti L, Sottini A, Paghera S, Quiros-Roldan E, Rossi C, Oler AJ, Tompkins MF, Alba C, Vandernoot I, Goffard JC, Smits G, Migeotte I, Haerynck F, Soler-Palacin P, Martin-Nalda A, Colobran R, Morange PE, Keles S, Çölkesen F, Ozcelik T, Yasar KK, Senoglu S, Karabela ?N, Gallego CR, Novelli G, Hraiech S, Tandjaoui-Lambiotte Y, Duval X, Laouénan C,, Snow AL, Dalgard CL, Milner J, Vinh DC, Mogensen TH, Marr N, Spaan AN, Boisson B, Boisson-Dupuis S, Bustamante J, Puel A, Ciancanelli M, Meyts I, Maniatis T, Soumelis V, Amara A, Nussenzweig M, García-Sastre A, Krammer F, Pujol A, Duffy D, Lifton R, Zhang SY, Gorochov G, Béziat V, Jouanguy E, Sancho-Shimizu V, Rice CM, Abel L, Notarangelo LD, Cobat A, Su HC, Casanova JL COVID-STORM Clinicians, COVID Clinicians, Imagine COVID Group, French COVID Cohort Study Group, CoV-Contact Cohort, Amsterdam UMC Covid-19, Biobank, COVID Human Genetic Effort, NIAID-USUHS, TAGC COVID Immunity Group

Abstract

Clinical outcome upon infection with SARS-CoV-2 ranges from silent infection to lethal COVID-19. We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern TLR3- and IRF7-dependent type I interferon (IFN) immunity to influenza virus, in 659 patients with life-threatening COVID-19 pneumonia, relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally define LOF variants in 23 patients (3.5%), aged 17 to 77 years, underlying autosomal recessive or dominant deficiencies. We show that human fibroblasts with mutations affecting this pathway are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.Copyright © 2020, American Association for the Advancement of Science.

Published
2020

21. Human Fibrinogen Concentrate and Fresh Frozen Plasma in the Management of Severe Acquired Hypofibrinogenemia in Children with Acute Lymphoblastic Leukemia: Results of a Retrospective Survey

Author

Giordano, P, Grassi, M, Saracco, P, Luciani, M, Colombini, A, Testi, A, Micalizzi, C, Petruzziello, F, Putti, M, Casale, F, Consarino, C, Mura, R, Mastrodicasa, E, Notarangelo, L, Onofrillo, D, Pollio, B, Rizzari, C, Tafuri, S, De Leonardis, F, Corallo, P, Santoro, N, Testi, AM, Putti, MC, Mura, RM, Notarangelo, LD, Corallo, PC, Giordano, P, Grassi, M, Saracco, P, Luciani, M, Colombini, A, Testi, A, Micalizzi, C, Petruzziello, F, Putti, M, Casale, F, Consarino, C, Mura, R, Mastrodicasa, E, Notarangelo, L, Onofrillo, D, Pollio, B, Rizzari, C, Tafuri, S, De Leonardis, F, Corallo, P, Santoro, N, Testi, AM, Putti, MC, Mura, RM, Notarangelo, LD, and Corallo, PC

Abstract

Objective of the Study:In this study we aimed to retrospectively evaluate how centers, belonging to the Associazione Italiana Ematologia e Oncologia Pediatrica (AIEOP), manage severe acquired hypofibrinogenemia in children with acute lymphoblastic leukemia, particularly evaluating the therapeutic role of human fibrinogen concentrate (HFC) and fresh frozen plasma (FFP).Methods:We conducted a survey among AIEOP centers; thereafter, we collected and analyzed data with regard to the treatment of episodes of severe acquired hypofibrinogenemia occurring during the induction and reinduction phases of the AIEOP-BFM ALL 2009 protocol.Results:In total, 15 of the 37 AIEOP centers invited to join the survey agreed to collect the data, with 10 and 5 centers declaring to react to severe acquired hypofibrinogenemia (<70 mg/dL) by administering HFC or FFP, respectively. Of the 150 episodes of severe hypofibrinogenemia occurring in 101 patients, 47.3% were treated with HFC and 52.7% with FFP, with a normalization of fibrinogen levels achieved in greater proportion and in a shorter amount of time in the HFC group as compared with the FFP group. None of the patients presented with bleeding or thrombosis during the observation period.Conclusions:Even with the limitations of the retrospective nature of this study, HFC seems to be a safe and effective alternative to FFP for replacement therapy in case of severe hypofibrinogenemia in children with acute lymphoblastic leukemia.

Published
2019

22. Prevalence and clinical challenges among adults with primary immunodeficiency and recombination-activating gene deficiency

Author

Lawless, D, Geier, CB, Farmer, JR, Lango Allen, H, Thwaites, D, Atschekzei, F, Brown, M, Buchbinder, D, Burns, SO, Butte, MJ, Csomos, K, Deevi, SVV, Egner, W, Ehl, S, Eibl, MM, Fadugba, O, Foldvari, Z, Green, DM, Henrickson, SE, Holland, SM, John, T, Klemann, C, Kuijpers, TW, Moreira, F, Piller, A, Rayner-Matthews, P, Romberg, ND, Sargur, R, Schmidt, RE, Schröder, C, Schuetz, C, Sharapova, SO, Smith, KGC, Sogkas, G, Speckmann, C, Stirrups, K, Thrasher, AJ, Wolf, HM, Notarangelo, LD, Anwar, R, Boyes, J, Ujhazi, B, NIHR BioResource - Rare Diseases Consortium, Thaventhiran, J, Walter, JE, Savic, S, Lango Allen, Hana [0000-0002-7803-8688], Smith, Kenneth [0000-0003-3829-4326], Johnson, Kathleen [0000-0002-6823-3252], Thaventhiran, James [0000-0001-8616-074X], and Apollo - University of Cambridge Repository

Subjects
Adult, DNA-Binding Proteins, Homeodomain Proteins, Immunologic Deficiency Syndromes, Prevalence, Humans, Nuclear Proteins
Published
2018
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24. Efficacy of lentivirus-mediated gene therapy in an Omenn syndrome recombination-activating gene 2 mouse model is not hindered by inflammation and immune dysregulation

Author

Capo, V, Castiello, M, Fontana, E, Penna, S, Bosticardo, M, Draghici, E, Poliani, L, Sergi Sergi, L, Rigoni, R, Cassani, B, Zanussi, M, Carrera, P, Uva, P, Dobbs, K, Sacchetti, N, Notarangelo, L, van Til, N, Wagemaker, G, Villa, A, Castiello, MC, Poliani, LP, Notarangelo, LD, van Til N. P., Capo, V, Castiello, M, Fontana, E, Penna, S, Bosticardo, M, Draghici, E, Poliani, L, Sergi Sergi, L, Rigoni, R, Cassani, B, Zanussi, M, Carrera, P, Uva, P, Dobbs, K, Sacchetti, N, Notarangelo, L, van Til, N, Wagemaker, G, Villa, A, Castiello, MC, Poliani, LP, Notarangelo, LD, and van Til N. P.

Abstract

Background: Omenn syndrome (OS) is a rare severe combined immunodeficiency associated with autoimmunity and caused by defects in lymphoid-specific V(D)J recombination. Most patients carry hypomorphic mutations in recombination-activating gene (RAG) 1 or 2. Hematopoietic stem cell transplantation is the standard treatment; however, gene therapy (GT) might represent a valid alternative, especially for patients lacking a matched donor. Objective: We sought to determine the efficacy of lentiviral vector (LV)–mediated GT in the murine model of OS (Rag2 R229Q/R229Q ) in correcting immunodeficiency and autoimmunity. Methods: Lineage-negative cells from mice with OS were transduced with an LV encoding the human RAG2 gene and injected into irradiated recipients with OS. Control mice underwent transplantation with wild-type or OS-untransduced lineage-negative cells. Immunophenotyping, T-dependent and T-independent antigen challenge, immune spectratyping, autoantibody detection, and detailed tissue immunohistochemical analyses were performed. Results: LV-mediated GT allowed immunologic reconstitution, although it was suboptimal compared with that seen in wild-type bone marrow (BM)−transplanted OS mice in peripheral blood and hematopoietic organs, such as the BM, thymus, and spleen. We observed in vivo variability in the efficacy of GT correlating with the levels of transduction achieved. Immunoglobulin levels and T-cell repertoire normalized, and gene-corrected mice responded properly to challenges in vivo. Autoimmune manifestations, such as skin infiltration and autoantibodies, dramatically improved in GT mice with a vector copy number/genome higher than 1 in the BM and 2 in the thymus. Conclusions: Our data show that LV-mediated GT for patients with OS significantly ameliorates the immunodeficiency, even in an inflammatory environment.

Published
2018

26. Autoimmune neutropenia of childhood secondary to other autoimmune disorders: Data from the Italian neutropenia registry

Author

Farruggia, P, Puccio, G, Fioredda, F, Lanza, T, Porretti, L, Ramenghi, U, Barone, A, Bonanomi, S, Finocchi, A, Ghilardi, R, Ladogana, S, Marra, N, Martire, B, Notarangelo, Ld, Onofrillo, D, Pillon, M, Russo, G, Lo Valvo, L, Serafinelli, J, Tucci, F, Zunica, F, Verzegnassi, F, and Dufour, C

Subjects
Male, Neutropenia, Infant, Newborn, Immunoglobulins, Intravenous, Immunoglobulins, Infant, Diseases, Infant, Premature, Diseases, Hematology, Newborn, Autoimmune Diseases, Child, Disease Susceptibility, Female, Humans, Immunosuppressive Agents, Infant, Premature, Italy, Prevalence, Registries, Settore MED/38, Intravenous, Premature
Published
2017

27. Diagnosis and management of newly diagnosed childhood autoimmune haemolytic anaemia. Recommendations from the Red Cell Study Group of the Paediatric Haemato-Oncology Italian Association

Author

Ladogana, S, Maruzzi, Maria Pia, Samperi, Pietro, Perrotta, S, Del Vecchio, Gc, Notarangelo, Ld, Farruggia, P, Verzegnassi, F, Masera, N, Saracco, P, Fasoli, S, Miano, M, Girelli, Gabriella, Barcellini, W, Zanella, A, Russo, G., Ladogana, Saverio, Maruzzi, Matteo, Samperi, Piera, Perrotta, Silverio, Del Vecchio, Giovanni C, Notarangelo, Lucia D, Farruggia, Piero, Verzegnassi, Federico, Masera, Nicoletta, Saracco, Paola, Fasoli, Silvia, Miano, Maurizio, Girelli, Gabriella, Barcellini, Wilma, Zanella, Alberto, and Russo, Giovanna

Subjects
child, therapy, diagnosis, autoimmune haemolytic anaemia, child, DAT, diagnosis, therapy, Disease Management, Hematology, DAT, Guideline, Pediatrics, diagnosis therapy, Coombs Test, Immunoglobulin M, Italy, Humans, Blood Transfusion, Steroids, autoimmune haemolytic anaemia, Anemia, Hemolytic, Autoimmune, autoimmune haemolytic anaemia, child, DAT, diagnosis therapy, Societies, Medical
Abstract

Autoimmune haemolytic anaemia is an uncommon disorder to which paediatric haematology centres take a variety of diagnostic and therapeutic approaches. The Red Cell Working Group of the Italian Association of Paediatric Onco-haematology (Associazione Italiana di Ematologia ed Oncologia Pediatrica, AIEOP) developed this document in order to collate expert opinions on the management of newly diagnosed childhood autoimmune haemolytic anaemia.The diagnostic process includes the direct and indirect antiglobulin tests; recommendations are given regarding further diagnostic tests, specifically in the cases that the direct and indirect antiglobulin tests are negative. Clear-cut definitions of clinical response are stated. Specific recommendations for treatment include: dosage of steroid therapy and tapering modality for warm autoimmune haemolytic anaemia; the choice of rituximab as first-line therapy for the rare primary transfusion-dependent cold autoimmune haemolytic anaemia; the indications for supportive therapy; the need for switching to second-line therapy. Each statement is provided with a score expressing the level of appropriateness and the agreement among participants.

Published
2017

28. Perceived challenges and attitudes to regimen and product selection from Italian haemophilia treaters: the 2013 AICE survey

Author

Franchini, M, Coppola, A, Rocino, A, Zanon, E, Morfini, M, Italian Association of Haemophilia Centers AICE Working Group, Accorsi, A, Aru, Ab, Biasoli, C, Cantori, I, Castaman, G, Cesaro, S, Ciabatta, C, De Cristofaro, R, Delios, G, Di Minno, G, D'Incà, M, Dragani, A, Ettorre, Cp, Gagliano, F, Gamba, G, Gandini, G, Giordano, P, Giuffrida, G, Gresele, P, Latella, C, Luciani, M, Margaglione, M, Marietta, M, Mazzucconi, Maria Gabriella, Messina, M, Molinari, Ac, Notarangelo, Ld, Oliovecchio, E, Peyvandi, F, Piseddu, G, Rossetti, G, Rossi, V, Santagostino, E, Schiavoni, M, Schinco, P, Serino, Ml, Tagliaferri, A, Testa, S., Franchini, M, Coppola, A, Rocino, A, Zanon, E, Morfini, M, Accorsi, A, Aru, Ab, Biasoli, C, Cantori, I, Castaman, G, Cesaro, S, Ciabatta, C, De Cristofaro, R, Delios, G, DI MINNO, Giovanni, D'Incà, M, Dragani, A, Ettorre, Cp, Gagliano, F, Gamba, G, Gandini, G, Giordano, P, Giuffrida, G, Gresele, P, Latella, C, Luciani, M, Margaglione, M, Marietta, M, Mazzucconi, Mg, Messina, M, Molinari, Ac, Notarangelo, Ld, Oliovecchio, E, Peyvandi, F, Piseddu, G, Rossetti, G, Rossi, V, Santagostino, E, Schiavoni, M, Schinco, P, Serino, Ml, Tagliaferri, A, and Testa, S.

Subjects
Haemophilia, Pediatrics, medicine.medical_specialty, factor concentrates, haemophilia treatment, inhibitor, prophylaxis, survey, viral safety, Blood Coagulation Factors, Health Care Surveys, Hemophilia A, Humans, Italy, Practice Patterns, Physicians', Surveys and Questionnaires, Hospitals, Special, Medical Staff, Hospital, Practice Patterns, NO, Hospital, Haemophilia A, Medical Staff, Medicine, Genetics (clinical), Clotting factor, Physicians', Special, Treatment regimen, business.industry, Settore MED/09 - MEDICINA INTERNA, Hematology, General Medicine, medicine.disease, Blood coagulation factors, Hospitals, Clinical Practice, Regimen, Family medicine, Product selection, business
Abstract

Summary Despite great advances in haemophilia care in the last 20 years, a number of questions on haemophilia therapy remain unanswered. These debated issues primarily involve the choice of the product type (plasma-derived vs. recombinant) for patients with different characteristics: specifically, if they were infected by blood-borne virus infections, and if they bear high or low risk of inhibitor development. In addition, the most appropriate treatment regimen in non-inhibitor and inhibitor patients compel physicians operating at the haemophilia treatment centres (HTCs) to take important therapeutic decisions, which are often based on their personal clinical experience rather than on evidence-based recommendations from published literature data. To know the opinion on the most controversial aspects in haemophilia care of Italian expert physicians, who are responsible for common clinical practice and therapeutic decisions, we have conducted a survey among the Directors of HTCs affiliated to the Italian Association of Haemophilia Centres (AICE). A questionnaire, consisting of 19 questions covering the most important topics related to haemophilia treatment, was sent to the Directors of all 52 Italian HTCs. Forty Directors out of 52 (76.9%) responded, accounting for the large majority of HTCs affiliated to the AICE throughout Italy. The results of this survey provide for the first time a picture of the attitudes towards clotting factor concentrate use and product selection of clinicians working at Italian HTCs.

Published
2014

32. AUTOIMMUNE NEUTROPENIA OF INFANCY: DATA FROM THE ITALIAN NEUTROPENIA REGISTRY

Author

Farruggia, P, Fioredda, F, Puccio, G, Porretti, L, Lanza, T, Ferro, F, Barone, A, Bonanomi, S, Davitto, M, Ghilardi, R, Ladogana, S, Mandaglio, R, Marra, N, Martire, B, Notarangelo, Ld, Onofrillo, D, Pillon, M, Ramenghi, U, Robustelli, G, Russo, G, Tucci, F, Macaluso, A, and Dufour, C

Published
2015

34. Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States

Author

Kwan, A, Abraham, RS, Currier, R, Brower, A, Andruszewski, K, Abbott, JK, Baker, M, Ballow, M, Bartoshesky, LE, Bonilla, FA, Brokopp, C, Brooks, E, Caggana, M, Celestin, J, Church, JA, Comeau, AM, Connelly, JA, Cowan, MJ, Cunningham-Rundles, C, Dasu, T, Dave, N, De La Morena, MT, Duffner, U, Fong, CT, Forbes, L, Freedenberg, D, Gelfand, EW, Hale, JE, Hanson, IC, Hay, BN, Hu, D, Infante, A, Johnson, D, Kapoor, N, Kay, DM, Kohn, DB, Lee, R, Lehman, H, Lin, Z, Lorey, F, Abdel-Mageed, A, Manning, A, McGhee, S, Moore, TB, Naides, SJ, Notarangelo, LD, Orange, JS, Pai, SY, Porteus, M, Rodriguez, R, Romberg, N, Routes, J, Ruehle, M, Rubenstein, A, Saavedra-Matiz, CA, Scott, G, Scott, PM, Secord, E, Seroogy, C, Shearer, WT, Siegel, S, Silvers, SK, Stiehm, ER, Sugerman, RW, Sullivan, JL, Tanksley, S, Tierce, ML, Verbsky, J, Vogel, B, Walker, R, Walkovich, K, Walter, JE, Wasserman, RL, Watson, MS, Weinberg, GA, Weiner, LB, Wood, H, Yates, AB, and Puck, JM

Abstract

Importance: Newborn screening for severe combined immunodeficiency (SCID) using assays to detect T-cell receptor excision circles (TRECs) began in Wisconsin in 2008, and SCID was added to the national recommended uniform panel for newborn screened disorders in 2010. Currently 23 states, the District of Columbia, and the Navajo Nation conduct population-wide newborn screening for SCID. The incidence of SCID is estimated at 1 in 100 000 births. Objectives: To present data from a spectrum of SCID newborn screening programs, establish population-based incidence for SCID and other conditions with T-cell lymphopenia and document early institution of effective treatments. DESIGN Epidemiological and retrospective observational study. Setting: Representatives in states conducting SCID newborn screening were invited to submit their SCID screening algorithms, test performance data and deidentified clinical and laboratory information regarding infants screened and cases with nonnormal results. Infants born from the start of each participating program from January 2008 through the most recent evaluable date prior to July 2013 were included. Representatives from 10 states plus the Navajo Area Indian Health Service contributed data from 3 030 083 newborns screened with a TREC test. Main Outcomes and Measures: Infants with SCID and other diagnoses of T-cell lymphopenia were classified. Incidence and, where possible, etiologies were determined. Interventions and survival were tracked. Results: Screening detected 52 cases of typical SCID, leaky SCID, and Omenn syndrome, affecting 1 in 58 000 infants (95%CI, 1/46 000-1/80 000). Survival of SCID-affected infants through their diagnosis and immune reconstitution was 87%(45/52), 92%(45/49) for infants who received transplantation, enzyme replacement, and/or gene therapy. Additional interventions for SCID and non-SCID T-cell lymphopenia included immunoglobulin infusions, preventive antibiotics, and avoidance of live vaccines. Variations in definitions and follow-up practices influenced the rates of detection of non-SCID T-cell lymphopenia. Conclusions and Relevance: Newborn screening in 11 programs in the United States identified SCID in 1 in 58 000 infants, with high survival. The usefulness of detection of non-SCID T-cell lymphopenias by the same screening remains to be determined. Copyright © 2014 American Medical Association. All rights reserved.

Published
2014
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36. Aplasie midollari acquisite in età pediatrica: Raccomandazioni diagnostico-terapeutiche [Acquired aplastic anaemia in children: Diagnostic-therapeutic recommendations]

Author

Barone, A, Lucarelli, A, Onofrillo, D, Verzegnassi, F, Bonanomi, S, Cesaro, S, Cugno, C, Fioredda, F, Iori, Ap, Ladogana, S, Locasciulli, A, Longoni, D, Lanciotti, M, Macaluso, A, Mandaglio, R, Marra, N, Martire, B, Maruzzi, M, Menna, G, Notarangelo, Ld, Palazzi, G, Pillon, M, Ramenghi, U, Russo, Giovanna, Svahn, J, Timeus, F, Tucci, F, Zecca, M, Farruggia, P, Dufour, C, and Saracco, P.

Published
2014

37. Acquired aplastic anaemia in children: Diagnostic-therapeutic recommendations

Author

Barone, A, Lucarelli, A, Onofrillo, D, Verzegnassi, F, Bonanomi, S, Longoni, D, Cesaro, S, Cugno, C, Zecca, M, Fioredda, F, Svahn, J, Dufour, C, Iori, Ap, Ladogana, S, Maruzzi, M, Locasciulli, A, Lanciotti, M, Macaluso, A, Mandaglio, R, Marra, N, Menna, G, Martire, B, Notarangelo, Ld, Palazzi, G, Pillon, M, Ramenghi, Ugo, Saracco, P, Russo, G, Timeus, F, Tucci, F, and Farruggia, P.

Subjects
Acquired aplastic anemia, Childhood
Published
2014

47. Platelet diameters in inherited thrombocytopenias: analysis of 376 patients with all known disorders

Author

Noris, P, Biino, G, Pecci, A, Civaschi, E, Savoia, A, Seri, M, Melazzini, F, Loffredo, G, Russo, G, Bozzi, V, Notarangelo, Ld, Gresele, P, Heller, Pg, Pujol Moix, N, Kunishima, S, Cattaneo, M, Bussel, J, De Candia, Erica, Cagioni, C, Ramenghi, U, Barozzi, S, Fabris, F, Balduini, Cl, De Candia, Erica (ORCID:0000-0003-0942-2819), Noris, P, Biino, G, Pecci, A, Civaschi, E, Savoia, A, Seri, M, Melazzini, F, Loffredo, G, Russo, G, Bozzi, V, Notarangelo, Ld, Gresele, P, Heller, Pg, Pujol Moix, N, Kunishima, S, Cattaneo, M, Bussel, J, De Candia, Erica, Cagioni, C, Ramenghi, U, Barozzi, S, Fabris, F, Balduini, Cl, and De Candia, Erica (ORCID:0000-0003-0942-2819)

Abstract

Abnormalities of platelet size are one of the distinguishing features of inherited thrombocytopenias (ITs), and evaluation of blood films is recommended as an essential step for differential diagnosis of these disorders. Nevertheless, what we presently know about this subject is derived mainly from anecdotal evidence. To improve knowledge in this field, we evaluated platelet size on blood films obtained from 376 patients with all 19 forms of IT identified so far and found that these conditions differ not only in mean platelet diameter, but also in platelet diameter distribution width and the percentage of platelets with increased or reduced diameters. On the basis of these findings, we propose a new classification of ITs according to platelet size. It distinguishes forms with giant platelets, with large platelets, with normal or slightly increased platelet size, and with normal or slightly decreased platelet size. We also measured platelet diameters in 87 patients with immune thrombocytopenia and identified cutoff values for mean platelet diameter and the percentage of platelets with increased or reduced size that have good diagnostic accuracy in differentiating ITs with giant platelets and with normal or slightly decreased platelet size from immune thrombocytopenia and all other forms of IT

Published
2014

50. Omenn syndrome: Inflammation in leaky severe combined immunodeficiency

Author

Villa A, Notarangelo LD, Roifman CM. J Allergy Clin Immunol. 122:1082-1086, and 2008

Subjects
Genotype, DCLRE1C, Immunology, LIG4, Biology, SCID, Recombination-activating gene, Autoimmune Diseases, Th2 Cells, Immune system, Eosinophilia, medicine, Humans, Immunology and Allergy, Immunodeficiency, Inflammation, Severe combined immunodeficiency, Immunoglobulin E, medicine.disease, Autoimmune regulator, Omenn syndrome, Phenotype, Severe Combined Immunodeficiency, mutation, Dermatitis, Exfoliative
Abstract

Omenn syndrome (OS) was reported until recently as a distinct form (phenotype and genotype) of severe combined immunodeficiency (SCID). Similar to other patients with SCID, patients with OS present early in infancy with viral or fungal pneumonitis, chronic diarrhea, and failure to thrive. Unlike typical SCID, patients with OS have enlarged lymphoid tissue, severe erythroderma, increased IgE levels, and eosinophilia. The inflammation observed in these patients is believed to be triggered by clonally expanded T cells, which are predominantly of the T H 2 type. These abnormal T cells, in the absence of proper regulation by other components of the immune system, secrete a host of cytokines that promote autoimmune as well as allergic inflammation. The emergence of these T-cell clones occurs in patients with hypomorphic mutations in recombination activating gene 1 or 2, but not in patients with deleterious mutations in these enzymes which render them inactive. Recently, OS was also identified in a growing list of other leaky SCIDs with mutations in RNA component of mitochondrial RNA processing endoribonuclease , adenosine deaminase , IL-2 receptor γ , IL-7 receptor α , ARTEMIS , and DNA ligase 4 . This new information revealed OS is a distinct inflammatory process that can be associated with genetically diverse leaky SCIDS.

Published
2008
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